TY - JOUR
T1 - Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin
AU - Gage, B. F.
AU - Eby, C.
AU - Johnson, J. A.
AU - Deych, E.
AU - Rieder, M. J.
AU - Ridker, P. M.
AU - Milligan, P. E.
AU - Grice, G.
AU - Lenzini, P.
AU - Rettie, A. E.
AU - Aquilante, C. L.
AU - Grosso, L.
AU - Marsh, S.
AU - Langaee, T.
AU - Farnett, L. E.
AU - Voora, D.
AU - Veenstra, D. L.
AU - Glynn, R. J.
AU - Barrett, A.
AU - McLeod, H. L.
PY - 2008/9
Y1 - 2008/9
N2 - Initiation of warfarin therapy using trial-and-error dosing is problematic. Our goal was to develop and validate a pharmacogenetic algorithm. In the derivation cohort of 1,015 participants, the independent predictors of therapeutic dose were: VKORC1 polymorphism -1639/3673 G>A (-28% per allele), body surface area (BSA) (+11% per 0.25 m2), CYP2C9*3 (-33% per allele), CYP2C9*2 (-19% per allele), age (-7% per decade), target international normalized ratio (INR) (+11% per 0.5 unit increase), amiodarone use (-22%), smoker status (+10%), race (-9%), and current thrombosis (+7%). This pharmacogenetic equation explained 53-54% of the variability in the warfarin dose in the derivation and validation (N= 292) cohorts. For comparison, a clinical equation explained only 17-22% of the dose variability (P < 0.001). In the validation cohort, we prospectively used the pharmacogenetic-dosing algorithm in patients initiating warfarin therapy, two of whom had a major hemorrhage. To facilitate use of these pharmacogenetic and clinical algorithms, we developed a nonprofit website, http://www.WarfarinDosing.org.
AB - Initiation of warfarin therapy using trial-and-error dosing is problematic. Our goal was to develop and validate a pharmacogenetic algorithm. In the derivation cohort of 1,015 participants, the independent predictors of therapeutic dose were: VKORC1 polymorphism -1639/3673 G>A (-28% per allele), body surface area (BSA) (+11% per 0.25 m2), CYP2C9*3 (-33% per allele), CYP2C9*2 (-19% per allele), age (-7% per decade), target international normalized ratio (INR) (+11% per 0.5 unit increase), amiodarone use (-22%), smoker status (+10%), race (-9%), and current thrombosis (+7%). This pharmacogenetic equation explained 53-54% of the variability in the warfarin dose in the derivation and validation (N= 292) cohorts. For comparison, a clinical equation explained only 17-22% of the dose variability (P < 0.001). In the validation cohort, we prospectively used the pharmacogenetic-dosing algorithm in patients initiating warfarin therapy, two of whom had a major hemorrhage. To facilitate use of these pharmacogenetic and clinical algorithms, we developed a nonprofit website, http://www.WarfarinDosing.org.
UR - https://www.scopus.com/pages/publications/47949086046
U2 - 10.1038/clpt.2008.10
DO - 10.1038/clpt.2008.10
M3 - Article
C2 - 18305455
AN - SCOPUS:47949086046
SN - 0009-9236
VL - 84
SP - 326
EP - 331
JO - Clinical pharmacology and therapeutics
JF - Clinical pharmacology and therapeutics
IS - 3
ER -